6-42960723-C-T

Variant names:

• chr6-42960723-C-T
• rs10948059
• ENST00000858685.1:c.-45C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001318857.2(CNPY3-GNMT):​c.152-2039C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,461,390 control chromosomes in the GnomAD database, including 161,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (16635 hom., cov: 34)
  • Exomes 𝑓: 0.47 (144565 hom.)
• Consequence: CNPY3-GNMT NM_001318857.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.329
• Publications: 45 publications found

Genes affected

GNMT (HGNC:4415): (glycine N-methyltransferase) The protein encoded by this gene is an enzyme that catalyzes the conversion of S-adenosyl-L-methionine (along with glycine) to S-adenosyl-L-homocysteine and sarcosine. This protein is found in the cytoplasm and acts as a homotetramer. Defects in this gene are a cause of GNMT deficiency (hypermethioninemia). Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between the upstream CNPY3 (canopy FGF signaling regulator 3) gene and this gene and is represented with GeneID:107080644. [provided by RefSeq, Jan 2016]

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CNPY3-GNMT (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 6-42960723-C-T is Benign according to our data. Variant chr6-42960723-C-T is described in ClinVar as Benign. ClinVar VariationId is 1283888.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318857.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNPY3-GNMT	NM_001318857.2		c.152-2039C>T		intron	N/A	NP_001305786.1
	CNPY3-GNMT	NM_001318856.2		c.9-1489C>T		intron	N/A	NP_001305785.1
	CNPY3-GNMT	NM_001318858.2		c.152-2039C>T		intron	N/A	NP_001305787.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNMT	ENST00000858685.1		c.-45C>T		5_prime_UTR	Exon 1 of 6	ENSP00000528744.1
	GNMT	ENST00000858684.1		c.-45C>T		5_prime_UTR	Exon 1 of 6	ENSP00000528743.1
	PEX6	ENST00000970120.1		c.*1761G>A		3_prime_UTR	Exon 18 of 18	ENSP00000640179.1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69996 AN: 152082 Hom.: 16624 Cov.: 34

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.127

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.459

GnomAD2 exomes AF: 0.391 AC: 34529 AN: 88392 AF XY: 0.402

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.279

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.126

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.476

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.465 AC: 608822 AN: 1309190 Hom.: 144565 Cov.: 27 AF XY: 0.466 AC XY: 296459 AN XY: 636678

African (AFR) AF: 0.518 AC: 14913 AN: 28804

American (AMR) AF: 0.299 AC: 8786 AN: 29396

Ashkenazi Jewish (ASJ) AF: 0.421 AC: 8720 AN: 20714

East Asian (EAS) AF: 0.143 AC: 4857 AN: 33990

South Asian (SAS) AF: 0.461 AC: 31293 AN: 67854

European-Finnish (FIN) AF: 0.413 AC: 15092 AN: 36502

Middle Eastern (MID) AF: 0.492 AC: 2154 AN: 4374

European-Non Finnish (NFE) AF: 0.483 AC: 498517 AN: 1033036

Other (OTH) AF: 0.449 AC: 24490 AN: 54520

GnomAD4 genome AF: 0.460 AC: 70048 AN: 152200 Hom.: 16635 Cov.: 34 AF XY: 0.455 AC XY: 33823 AN XY: 74398

African (AFR) AF: 0.514 AC: 21351 AN: 41528

American (AMR) AF: 0.361 AC: 5529 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1452 AN: 3470

East Asian (EAS) AF: 0.127 AC: 659 AN: 5172

South Asian (SAS) AF: 0.432 AC: 2083 AN: 4824

European-Finnish (FIN) AF: 0.431 AC: 4564 AN: 10594

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.482 AC: 32744 AN: 67994

Other (OTH) AF: 0.457 AC: 966 AN: 2116

Alfa AF: 0.460 Hom.: 8007

Bravo AF: 0.455

Asia WGS AF: 0.290 AC: 1009 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.8
DANN	Benign	0.75
PhyloP100		-0.33
PromoterAI		-0.034	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10948059; hg19: chr6-42928461; COSMIC: COSV55102851;